Polysulfone-based hollow-fiber membrane with selective permeability

ABSTRACT

The present invention provides a polysulfone type hollow fiber membrane which is reliable in safety and stability of performance and is easily incorporated into a module, and thus can be suitably used in a highly water permeable blood purifier for use in a therapy of chronic renal failure. 
     The present invention relates to a polysulfone type selectively permeable hollow fiber membrane comprising a polysulfone type resin and a hydrophilic polymer as main components, and characterized in that
     (A) the content of the hydrophilic polymer in the uppermost layer of a surface of the polysulfone type hollow fiber membrane on the blood-contacting side is at least 1.1 times larger than the content of the hydrophilic polymer in the proximate layer of the surface on the blood-contacting side, and   (B) the content of the hydrophilic polymer in the uppermost layer of the other surface of the polysulfone type hollow fiber membrane, i.e., the reverse side of the surface on the blood-contacting side, is at least 1.1 times larger than the content of the hydrophilic polymer in the uppermost layer of the surface on the blood-contacting side.

The present patent application is filed claiming the priority based onthe Japanese Patent Application No. 2003-396408, and a whole of thecontents of this application should be incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to polysulfone type selectively permeablehollow fiber membranes which are reliable in safety and stability ofperformance and are easily incoporated into a module and which areparticularly suitable for use in blood purifiers. The present inventionalso pertains to the use of the polysulfone type selectively permeablehollow fiber membranes as blood purifiers, and a process formanufacturing the hollow fiber membranes.

BACKGROUND OF THE INVENTION

In the hemocatharsis for therapy of renal failure, etc., modules such ashemodialyzers, hemofilters and hemodiafilters, which comprise dialysismembrans or ultrafilter membranes as separators are widely used in orderto remove urinal toxic substances and waste products in blood. Dialysismembranes and ultrafilter membranes as separators are made up of naturalmaterials such as cellulose or the derivatives thereof (e.g., cellulosediacetate, cellulose triacetate, etc.) or synthetic polymers such aspolyslufone, polymethyl methacrylate, polyacrylonitrile, etc. Theimportance of modules comprising the hollow fiber membranes asseparators is very high in the field of dialyzers, in view of theadvantages such as the reduction of the amount of extracorporealcirculated blood, high efficiency of removing undesired substances inblood, and high productivity of manufacturing modules.

Highly water permeable polysulfone type resins have attracted publicattentions, because such resins are most suitable for the advanceddialysis technology, among the above-listed membrane materials. However,semipermeable membranes made up of a polysulfone resin alone are poor inaffinity with blood, inducing airlock phenomena, since the polysulfonetype resin is hydrophobic. Therefore, such semipermeable membranes asthey are can not be directly used for treating blood.

To solve this problem, there is proposed a method for impartinghydrophilicity to a membrane by blending a polysulfone type resin with ahydrophilic polymer: for example, a polyhydric alcohol such aspolyethylene glycol or the like is added to a polysulfone type resin(cf. JP-A-61-232860 and JP-A-58-114702); or otherwise, polyvinylpyrrolidone is added to a polysulfone type resin (cf. JP-B-5-54373 andJP-B-6-75667).

These methods are effective to solve the foregoing problem. However,finding of the optimum conditions for the hydrophilicity-impartingtechnique by blending a hydrophilic polymer is very important, becausethe concentration of the hydrophilic polymer in the inner surface of ahollow fiber membrane on the blood-contacting side and the concentrationof the hydrophilic polymer in the outer surface thereof give significantinfluence on the capacities of the hollow fiber membrane. For example,the compatibility of a hollow fiber membrane with blood can be ensuredby increasing the concentration of a hydrophilic polymer in the innersurface of the membrane, while too high a concentration of thehydrophilic polymer in the inner surface of the membrane increases theamount of the hydrophilic polymer eluted into blood. Undesirably, theaccumulation of the eluted hydrophilic polymer induces side effects orcomplications over a long period of dialysis therapy.

On the other hand, too high a concentration of the hydrophilic polymerin the outer surface of the membrane induces a danger of the invasion ofhighly hydrophilic endotoxin in a dialyzate into the blood side. As aresult, side effects such as fever, etc. are induced, or the hydrophilicpolymer in the outer surfaces of the hollow fiber membranes permits thesticking of such membranes to one another while the membranes are beingdried, which results in a new problem that the incorporation of suchmembranes into a module becomes hard.

On the contrary, a lower concentration of the hydrophilic polymer in theouter surface of the hollow fiber membrane is preferable, since theinvasion of endotoxin into the blood side can be suppressed. However,the hydrophilicity of the outer surface of the hollow fiber membranebecomes lower, which causes a problem in that the outer surface of thehollow fiber membrane becomes poor in compatibility with physiologicalsaline for use in wetting the membrane, when a bundle of dried hollowfiber membranes is wetted and incorporated into a module. As a result,undesirably, the priming of the membranes (purging the membranes of anair when wetting the same) may become lower in efficiency.

There is disclosed a method for solving these problems (cf.JP-A-6-165926): that is, the concentration of a hydrophilic polymer inthe dense layer of the inner surface of a hollow fiber membrane isadjusted within a specified range, and the mass ratio of the hydrophilicpolymer in the dense layer of the inner surface of the membrane is atleast 1.1 times larger than the mass ratio of the hydrophilic polymer inthe outer surface of the membrane. In particular, this method is basedon a technical idea to increase the mass ratio of the hydrophilicpolymer in the dense layer of the inner surface of the membrane tothereby improve the compatibility thereof with blood, and to decreasethe mass ratio of the hydrophilic polymer in the outer surface of themembrane to thereby suppress the sticking of the hollow fiber membraneswhich would occur when drying the membranes. This technique also solvesanother problem: i.e., the invasion of endotoxin in a dialyzate into theblood side is inhibited. However, there still remains unsolved theproblem that the priming of the membrane tends to lower because of toolow a mass ratio of the hydrophilic polymer in the outer surface of themembrane. It is therefore needed to solve this problem.

There is disclosed another method of solving the problem of the invasionof endotoxin in a dialyzate into the blood side (cf. JP-A-2001-38170).In this method, the contents of hydrophilic polymers in the proximatelayers of the inner surface and the outer surface, and the intermediatelayer of a hollow fiber membrane having an uniform membrane structure,determined by infrared-absorbing analysis method, are specified so as tosuppress the invasion of endotoxin into the blood side. However, also,this method can not solve the problem of lower priming of the membrane,as well as the former method. In addition, there is a further problem inthat the larger size pores of the outer surface of the hollow fibermembrane lower the pressure resistance of the membrane. Therefore, sucha membrane has a danger of bursting when used for hemodiafiltration orthe like in which the pressure of a fluid is higher than that in theconventional therapies.

There are further disclosed methods for improving the compatibility ofmembranes with blood and for reducing the amount of hydrophilic polymerseluted into blood, by specifying the contents of the hydrophilicpolymers in the inner surfaces of hollow fiber membranes (cf.JP-A-6-296686, JP-A-11-309355 and JP-A-2000-157852).

However, any of the above patent literature does not teach the ratio ofthe hydrophilic polymer present in the outer surface of the hollow fibermembrane, i.e., the reverse side of the blood-contacting side of thehollow fiber membrane, and thus, any of the inventions of the abovepublications is not able to improve all the problems attributed to theratio of the hydrophilic polymer present in the outer surface of thehollow fiber membrane.

There is disclosed a method of solving the problem of the invasion ofendotoxin into the blood side, out of the foregoing problems (cf.JP-A-2000-254222). This method is devised by taking advantage of theproperties of endotoxin which has a hydrophobic moiety in the moleculeand which is apt to be adsorbed onto a hydrophobic material.Specifically, in this method, the ratio of a hydrophilic polymer to ahydrophobic polymer in the outer surface of a hollow fiber membrane isadjusted to 5 to 25%. Surely, this method is effective to suppress theinvasion of endotoxin into the side of blood. However, it is needed toremove the hydrophilic polymer in the outer surface of the membrane bywashing, so as to impart this feature to the membrane. Accordingly, longtreating time is required for this washing, which is disadvantageous incost. For example, in an Example of the invention of the above patentpublication, a hollow fiber membrane is washed by showering with hotwater of 60° C. for one hour and washed with hot water of 110° C. forone hour.

This method of decreasing the amount of the hydrophilic polymer in theouter surface of the membrane is effective to inhibit the invasion ofendotoxin into the side of blood. However, the hydrophilicity of theouter surface of the membrane becomes lower, which causes the followingdisadvantage: when a bundle of hollow fiber membranes dried afterincorporated into a module is again wetted and incorporated into amodule, the hollow fiber membranes become poor in compatibility withphysiological saline for wetting the membranes. Undesirably, this methodmay induce poor priming, i.e., insufficient purging the membranes of anair during a membrane-wetting step. For example, there are disclosedmethods of improving this problem, in which a hydrophilic compound suchas glyceline or the like is blended (cf. JP-A-2001-190934 and JapanesePatent No. 3193262). These methods, however, have problems in that thehydrophilic compound behaves as a foreign matter during dialysis andalso tends to deteriorate by light or the like, which gives an adverseinfluence on the storage stability of a module, and also in that thehydrophilic compound hinders an adhesive from bonding for fixing abundle of hollow fiber membranes in a module when the membranes areincorporated into the module.

There are disclosed methods of avoiding the sticking of hollow fibermembranes, i.e., another problem out of the foregoing problems: in anyof these methods, the rate of pore area of the outer surface of amembrane is adjusted to 25% or more (cf. JP-A-2001-38170 andJP-A-7-289863). While these methods are surely effective to avoid thesticking of the hollow fiber membranes, the strength of the membranesbecomes lower due to the higher rate of pore area, which may lead to theleakage of blood or the like.

Further, a method by specifying the rate of pore area and the pore areaof the outer surface of a membrane is disclosed (cf. JP-A-2000-140589)

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide polysulfone typeselectively permeable hollow fiber membranes which are reliable insafety and performance stability and are incorporated into a module withease and which are especially suitable for use in a blood purifier.

As a result of the present inventors' intensive researches for solvingthe foregoing problems, the present invention is accomplished byproviding the following hollow fiber mebrane. That is, the presentinvention relates to a polysulfone type hollow fiber membrane comprisinga polysulfone type resin and a hydrophilic polymer as main components,and characterized in that

-   (A) the content of the hydrophilic polymer in the uppermost layer of    a surface of the polysulfone type hollow fiber membrane on the    blood-contacting side is at least 1.1 times larger than the content    of the hydrophilic polymer in the proximate layer of the same    surface of the membrane on the blood-contacting side; and that-   (B) the content of the hydrophilic polymer in the uppermost layer of    the other surface of the polysulfone type hollow fiber membrane,    i.e., the reverse side of the surface on the blood-contacting side,    is at least 1.1 times larger than the content of the hydrophilic    polymer in the uppermost layer of the surface of the membrane on the    blood-contacting side.

In one aspect of the present invention, the content of the hydrophilicpolymer in the uppermost layer of the surface of the membrane on theblood-contacting side is, in general, preferably 5 to 60 mass %, morepreferably 10 to 50 mass %, still more preferably 20 to 40 mass %. Thecontent of the hydrophilic polymer in the proximate layer adjacent tothe uppermost layer in the surface of the membrane is generally about 2to about 37 mass %, optimally about 5 to about 20 mass %. Further, thecontent of the hydrophilic polymer in the outer surface of the hollowfiber membrane is about 25 to about 50 mass % which is enough to controlthe content of the hydrophilic polymer in the uppermost layer of theother surface of the membrane, i.e., the reverse side of the surface onthe blood-contacting side, to be at least 1.1 times larger than thecontent of the hydrophilic polymer in the uppermost layer of the surfaceof the membrane on the blood-contacting side. The contents of thehydrophilic polymer in the respective layers as above are so selected asto adjust the hydrophilic polymer eluted from the hollow fiber membraneto be 10 ppm or less.

Advantageously, the polysulfone type hollow fiber membrane of thepresent invention is reliable in safety, performance stability and easeof incorporating into a module, and is suitably used in a highly waterpermeable hollow fiber membrane type blood purifier for hemodialysis foruse in therapy of chronic renal failure.

BEST MODES FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be explained in more detail.

The hollow fiber membrane to be used in the present invention comprisesa polysulfone type resin and a hydrophilic polymer. The polysulfone typeresin referred to in the present invention is the generic term of resinshaving sulfone bonds. Preferable examples of the polysulfone type resininclude, but not limited to, polysulfone resins and polyethersulfoneresins both of which comprise repeating units represented by the formula[I] or [II] and which are commercially available with ease.

Examples of the hydrophilic polymer referred to in the present inventioninclude materials such as polyethylene glycol, polyvinyl alcohol,polyvinyl pyrrolidone, carboxymethyl cellulose, polypropylene glycol,glycerin, starches, and derivatives thereof. In preferred embodiments ofthe present invention, polyvinyl pyrrolidone having a weight averagemolecular weight of 10,000 to 1,500,000 is used in view of safety andcost-effectiveness. In concrete, preferably used are polyvinylpyrrolidone having a molecular weight of 9,000 (K17), polyvinylpyrrolidone having a molecular weight of 45,000 (K30), polyvinylpyrrolidone having a molecular weight of 450,000 (K60), polyvinylpyrrolidone having a molecular weight of 900,000 (K80) and polyvinylpyrrolidone having a molecular weight of 1,200,000 (K90) which arecommercially available from BASF. Each of the above hydrophilic polymersmay be used alone or in combination with one or more of the same resinshaving different molecular weights, or with one or more of differentresins, according to an intended use, or in order to obtain intendedcapacities or structure.

In the present invention, (A) the content of the hydrophilic polymer inthe uppermost layer of a surface of the polysulfone type hollow fibermembrane on the blood-contacting side is at least 1.1 times larger thanthe content of the hydrophilic polymer in the proximate layer of thesurface of the membrane on the blood-contacting side, as mentionedabove. Preferably, the content of the hydrophilic polymer in theproximate layer, adjacent to the uppermost layer, of the surface of themembrane is about 2 to about 37 mass %, in order to control the contentof the hydrophilic polymer in the uppermost layer to be larger than thecontent of the hydrophilic polymer in the proximate layer and tooptimally control the content of the hydrophilic polymer in theuppermost layer to 20 to 40 mass %. Practically, the proper content ofthe hydrophilic polymer in the proximate layer of the surface of themembrane is about 5 to about 20 mass % because of this reason. Indetail, the multiplying factor of the difference in content is allowedup to maximum 10 or so. When the multiplying factor exceeds this limit,the diffusion and transfer of the hydrophilic polymer may reverselyproceed from the uppermost layer to the proximate layer in the surfaceof the membrane, and the manufacturing of a hollow fiber membrane havinga structure allowing such a multiplying factor is difficult. A propercontent of the hydrophilic polymer in the uppermost layer of the surfaceof the membrane on the blood-contacting side can be calculated simply bymultiplying the value of the proper content of the hydrophilic polymerin the proximate layer in the surface of the membrane, namely, 5 to 20mass %, by the value of a multiplying factor of about 1.1 to about 10.By doing so, the optimum value of 20 to 40 mass % is obtained for thecontent of the hydrophilic polymer in the above uppermost layer.Preferably, the hydrophilic polymer is contained in the uppermost layerin an amount which is usually about 1.1 to about 5 times larger, and asthe case may be, optimally about 1.2 to about 3 times larger than thecontent of the hydrophilic polymer in the proximate layer. Practically,the multiplying factor can be optionally selected in consideration ofthe capacities of the hollow fiber membrane. For example, when thecontent of the hydrophilic polymer in the proximate layer of the surfaceof the membrane is 5 mass % as the lower limit, the content of thehydrophilic polymer in the uppermost layer in the surface of themembrane may be appropriately 20 to 40 mass % which is equivalent to avalue 4 to 8 times larger than the content of the hydrophilic polymer inthe above proximate layer.

In the present invention, (B) the content of the hydrophilic polymer inthe uppermost layer of the other surface of the polysulfone type hollowfiber membrane, i.e., the reverse side of the surface on theblood-contacting side, is at least 1.1 times larger than the content ofthe hydrophilic polymer in the uppermost layer of the surface of themembrane on the blood-contacting side, as mentioned above. In thisregard, the content of the hydrophilic polymer in the outer surface ofthe hollow fiber membrane is preferably 25 to 50 mass %. When thecontent of the hydrophilic polymer in the outer surface of the membraneis too small, the amount of protein in blood adsorbed to the supportlayer of the hollow fiber membrane tends to increase, and undesirably,the compatibility of the membrane with blood and the permeability of themembrane tend to lower. On the contrary, when the content of thehydrophilic polymer in the outer surface of the membrane is too large,there may be higher possibility of the invasion of endotoxin in adialyzate into the blood side, which may induce side effects such asfever, etc. in a patient, or which may cause a disadvantage that themembranes are hardly incorporated into a module because of the stickingof such hollow fiber membranes due to the hydrophilic polymer in thesurfaces of the membranes, when the membranes are dried.

In the present invention, the ratio of the hydrophilic polymer to thepolysulfone type resin in the membrane is not particularly limited, andit may be optionally selected, in so far as sufficient hydrophilicityand high moisture content can be imparted to the hollow fiber membrane.Preferably, the mass ratio of the hydrophilic polymer is 1 to 20 mass %relative to 80 to 99 mass % of the polysulfone type resin. Morepreferably, the mass ratio of the hydrophilic polymer is 3 to 15 mass %relative to 85 to 97 mass % of the polysulfone type resin. When the massratio of the hydrophilic polymer is less than 1 mass %, thehydrophilicity-imparting effect may be poor. On the other hand, when themass ratio of the hydrophilic polymer exceeds 20 mass %, thehydrophilicity-imparting effect is saturated, and the amount of thehydrophilic polymer eluted from the membrane increases and may exceed 10ppm, as will be described later.

The foregoing preferred embodiments of the present invention will bedescribed in more detail based on the technical features. That is, in apreferred embodiment of the present invention, a polysulfone typeselectively permeable hollow fiber membrane which contains a hydrophilicpolymer and which simultaneously satisfies the following features can beobtained:

-   (1) the amount of the hydrophilic polymer eluted from the hollow    fiber membrane is 10 ppm or less;-   (2) the content of the hydrophilic polymer in the uppermost layer of    a surface of the polysulfone type hollow fiber membrane on the    blood-contacting side is 20 to 40 mass %;-   (3) the content of the hydrophilic polymer in the proximate layer of    the surface of the polysulfone type hollow fiber membrane on the    blood-contacting side is 5 to 20 mass %; and-   (4) the content of the hydrophilic polymer in the uppermost layer of    the other surface of the polysulfone type hollow fiber membrane,    i.e., the reverse side of the surface on the blood-contacting side,    is 25 to 50 mass %, and is at least 1.1 times larger than the    content of the hydrophilic polymer in the uppermost layer of the    inner surface of the membrane.

In the present invention, the amount of the hydrophilic polymer elutedfrom the hollow fiber membrane is preferably 10 ppm or less (feature 1).When this amount exceeds 10 ppm, there is a danger of inducing sideeffects or complications due to the eluted hydrophilic polymer over along period of dialysis therapy. To obtain this feature, for example,the ratios of the hydrophilic polymer to the hydrophobic polymer in therespective layers are controlled within the foregoing ranges, orotherwise, the conditions for manufacturing the hollow fiber membraneare optimized.

In the present invention, as mentioned above, the content of thehydrophilic polymer in the uppermost layer of the surface of thepolysulfone type hollow fiber membrane on the blood-contacting side ispreferably 20 to 40 mass % (feature 2). As long as the contents of thehydrophilic polymer and the differences in contents are controlled asdescribed above, the content of the hydrophilic polymer in the uppermostlayer of the surface of the polysulfone type hollow fiber membrane onthe blood-contacting side can be optionally selected within a wide rangeof 5 to 60 mass %, for example, 10 to 50 mass %. In order toadvantageously attain the effect of the present invention, preferably,the uppermost layer of the inner surface of the hollow fiber membranecomprises 60 to 80 mass % of the polysulfone type resin and 20 to 40mass % of the hydrophilic polymer as main components. When the contentof the hydrophilic polymer is less than 20 mass %, the hydrophilicity ofthe surface of the hollow fiber membrane on the blood-contacting sidebecomes lower, which leads to poor compatibility of the membrane withblood so that the blood tends to coagulates on the surface of the hollowfiber membrane. The coagulated thrombus clogs the hollow fiber membraneand degrades the separating capacity of the hollow fiber membrane orincreases the amount of the blood left to remain therein after used forhemodialysis. The content of the hydrophilic polymer in the uppermostlayer of the inner surface of the hollow fiber membrane is preferably 21mass % or more, more preferably 22 mass % or more, still more preferably23 mass % or more. On the other hand, when this content exceeds 40 mass%, the amount of the hydrophilic polymer eluted into the bloodincreases, and such eluted hydrophilic polymer has a danger of inducingside effects or complication over a long period of hemodialysis therapy.The content of the hydrophilic polymer in the uppermost layer of theinner surface of the hollow fiber membrane is preferably 39 mass % orless, more preferably 38 mass % or less, still more preferably 37 mass %or less.

In the present invention, the content of the hydrophilic polymer in theproximate layer of the surface of the polysulfone type hollow fibermembrane on the blood-contacting side is preferably 5 to 20 mass %, asmentioned above (feature 3). The proximate layer of the surface of thepolysulfone type hollow fiber membrane on the blood-contacting sidecomprises 60 to 99 mass % of the polysulfone type resin and 1 to 40 mass% of the hydrophilic polymer, as main components, which may beoptionally selected within the above ranges, respectively. The contentof the hydrophilic polymer is preferably 5 to 20 mass %, and in general,more preferably 7 to 18 mass %. The content of the hydrophilic polymerin the uppermost layer in the surface of the polysulfone type hollowfiber membrane on the blood-contacting side is preferably large from theviewpoint of compatibility with blood, as mentioned above. However,there is an antinomy in that the increase of the content of thehydrophilic polymer leads to the increase of the amount of thehydrophilic polymer eluted into the blood. Therefore, the content of thehydrophilic polymer is about 20 to about 40 mass %, which is selected inconsideration of the appropriate range thereof.

The content of the hydrophilic polymer in the proximate layer of theinner surface of the hollow fiber membrane may be selected within arelatively wide range of 1 to 40 mass %. However, there is adisadvantage when the content of the hydrophilic polymer in theproximate layer is larger than the content of the hydrophilic polymer inthe uppermost layer (for example, when the content of the hydrophilicpolymer in the uppermost layer is 30 mass %, and that in the proximatelayer, 35 mass %): that is, the diffusion and transfer of thehydrophilic polymer from the proximate layer to the uppermost layer ofthe inner surface of the membrane is activated, with the result that,undesirably, the content of the hydrophilic polymer in the uppermostlayer becomes larger than the predetermined value. To sum up, inconsideration of a mechanism which allows the hydrophilic polymer to besupplied to the uppermost layer by the amount of the hydrophilic polymerconsumed in the uppermost layer, through the diffusion and transfer ofthe hydrophilic polymer, the content of the hydrophilic polymer in theproximate layer of the surface of the membrane is relatively smallerthan that in the uppermost layer, and is preferably, for example, 19mass % or less, more preferably 18 mass % or less. When the content ofthe hydrophilic polymer in the proximate layer of the inner surface ofthe hollow fiber membrane is too small, it is impossible to supply thehydrophilic polymer from the proximate layer to the uppermost layer,which may lead to a danger of lowering the stability of thesolute-removing capacity or the blood compatibility of the hollow fibermembrane. The optimum content of the hydrophilic polymer in theproximate layer of the inner surface of the hollow fiber membrane is,therefore, more preferably 6 mass % or more, still more preferably 7mass % or more. In general, the content of the hydrophilic polymer inthe proximate layer of the surface of the hollow fiber membrane isslightly larger than the average content of the hydrophilic polymer inthe hollow fiber membrane of the present invention which comprises 80 to99 mass % of the polysulfone type polymer and 1 to 20 mass % of thehydrophilic polymer as the main components.

This feature 3 is one of the factors which make it possible to overcomethe foregoing antimony and to optimize the contents of the hydrophilicpolymer in the respective layers so as to eliminate the antimony, at ahigher level than any of the conventional techniques has done. Thefeature 3 is also one of the novel features of the present invention. Inother words, the content of the hydrophilic polymer in the uppermostlayer of the hollow fiber membrane, which dominantly affects the bloodcompatibility of the membrane, is set at the lowest level which allowsthe exhibition of the blood compatibility. However, there arises anotherproblem in that, although this content of the hydrophilic polymer in theuppermost layer can permit the exhibition of the initial bloodcompatibility, the hydrophilic polymer in the uppermost layer is elutedinto blood bit by bit during a long time of hemodialysis, whichgradually lowers the blood compatibility in the course of thehemodialysis. The persistency of the blood compatibility of thepolysulfone type hollow fiber membrane is improved by specifying thecontent of the hydrophilic polymer in the proximate layer of the surfaceof the hollow fiber membrane on the blood-contacting side. By specifyingthe content of the hydrophilic polymer in the proximate layer of thesurface of the hollow fiber membrane, there can be solved the foregoingproblems, i.e., the decrease of the content of the hydrophilic polymerin the uppermost layer due to the elution of the hydrophilic polymer ofthe uppermost layer into blood in association with the proceeding ofhemodialysis, and the aged deterioration of the blood compatibility ofthe membrane attributed to the above decrease of the content of thehydrophilic polymer. This method is based on the technical idea that thetransfer of the hydrophilic polymer in the proximate layer of thesurface of the hollow fiber membrane, to the uppermost layer thereof cancompensate for the decrease of the content of the hydrophilic polymer inthe uppermost layer. Accordingly, less than 5 mass % of the content ofthe hydrophilic polymer in the proximate layer of the surface of thehollow fiber membrane on the blood-contacting side may be possiblyinsufficient to suppress the deterioration of the consistency of theblood compatibility of the hollow fiber membrane. On the other hand,when the content of the hydrophilic polymer in the proximate layer ofthe surface of the hollow fiber membrane on the blood-contacting sideexceeds 20 mass %, the amount of the hydrophilic polymer eluted intoblood tends to increase, which may possibly induce side effects orcomplications over a long period of hemodialysis therapy. Hitherto,there has been no elucidation of the blood compatibility and the agedstability of the selective permeation of the hollow fiber membrane whichare determined by the proper contents of the hydrophilic polymer in theuppermost layer and the proximate layer of the surface of the hollowfiber membrane and the structure thereof. It is to be noted that thesematters have been elucidated exactly by the present inventors' novelfindings.

In the present invention, the content of the hydrophilic polymer in theuppermost layer of the other surface of the polysulfone type hollowfiber membrane, i.e., the reverse side of the surface on theblood-contacting side, is 25 to 50 mass %, and is preferably at least1.1 times larger than the content of the hydrophilic polymer in theuppermost layer of the inner surface of the membrane (feature 4), asmentioned above. Too small a content of the hydrophilic polymer in theouter surface of the hollow fiber membrane may possibly lower the bloodcompatibility and permeation capacity of the hollow fiber membrane,since the amount of protein in blood, adsorbed onto the support layer ofthe hollow fiber membrane, tends to increase. In case of dried hollowfiber membranes, the priming capacity of the membranes may become poor.The outer surface of the hollow fiber membrane may comprise 90 to 40mass % of the polysulfone type resin and 10 to 60 mass % of thehydrophilic polymer as the main components. Practically, the content ofthe hydrophilic polymer in the outer surface of the hollow fibermembrane is more preferably 27 mass % or more, still more preferably 29mass % or more. Too large a content of the hydrophilic polymer in theouter surface of the membrane, on the contrary, may induce higherpossibility of invasion of endotoxin in the dialyzate into the bloodside. As a result, side effects such as fever, etc. may be induced; orthe hollow fiber membranes tend to stick to one another because of thehydrophilic polymer present on the surfaces of the membranes when themembranes are dried, and this may make it hard to incorporate suchmembranes into a module. The content of the hydrophilic polymer in theouter surface of the hollow fiber membrane is more preferably 43 mass %or less, still more preferably 40 mass % or less.

As one aspect of the feature 4, the content of the hydrophilic polymerin the uppermost layer of the outer surface of the hollow fiber membraneis preferably at least 1.1 times larger than the content of thehydrophilic polymer in the uppermost layer of the inner surface thereof.The content of the hydrophilic polymer gives some influence on theshrinkage percentage of the hollow fiber membrane formed. With theincrease of the content of the hydrophilic polymer, the shrinkagepercentage of the resultant hollow fiber membrane tends to increase. Forexample, when the content of the hydrophilic polymer in the uppermostlayer of the inner surface of the membrane is larger than the content ofthe hydrophilic polymer in the uppermost layer of the outer surface ofthe membrane, the difference in shrinkage percentage between the innersurface and the outer surface of the membrane may cause microwrinkles onthe inner surface of the hollow fiber membrane or break the hollow fibermembrane. The wrinkles formed on the inner surface of the hollow fibermembrane facilitates the accumulation of the protein in blood on thesurface of the membrane, when the blood is allowed to flow into thehollow fiber membranes for hemodialysis. This may induce a problem thatthe permeation capacity of the membrane degrades with time. For thisreason, it is preferable to increase the content of the hydrophilicpolymer in the outer surface of the hollow fiber membrane so as to belarger than that in the inner surface thereof.

The hollow fiber membrane of the present invention further has a denselayer in the inner surface, and has a structure in which the sizes ofpores are gradually increased toward the outer surface of the membrane.Since the void ratio of the outer surface of the membrane is higher thanthat of the inner surface thereof, the shrinkage percentage of the outersurface of the membrane becomes larger. In consideration of thisinfluence, the content of the hydrophilic polymer in the uppermost layerof the outer surface of the membrane is preferably at least 1.1 times,more preferably at least 1.2 times, still more preferably at least 1.3times larger than that in the uppermost layer of the inner surface ofthe membrane.

For the reasons as described above, the better, the larger the contentof the hydrophilic polymer in the uppermost layer of the outer surfaceof the hollow fiber membrane. However, there may be some problems, whenthe content of the hydrophilic polymer in the uppermost layer of theouter surface of the hollow fiber membrane is 2.0 or more times largerthan that in the uppermost layer of the inner surface thereof: that is,the content of the hydrophilic polymer relative to the content of thepolysulfone type polymer becomes too large, which may lead to theinsufficient strength of the hollow fiber membrane, the sticking of thehollow fiber membranes to one another, the back flow of endotoxin duringhemodialysis and the elution of the hydrophilic polymer. The content ofthe hydrophilic polymer in the uppermost layer of the outer surface ofthe hollow fiber membrane is more preferably at most 1.9 times, stillmore preferably at most 1.8 times, far more preferably at most 1.7 timeslarger than that in the uppermost layer of the inner surface thereof.

In another aspect, the hydrophilic polymer is preferably crosslinked soas to be insoluble. There is no limit in selection of the crosslinkingmethod or the degree of crosslinking. For example, crosslinking byirradiation with γ-rays, electron rays or heat, or chemical crosslinkingis carried out. Above all, crosslinking by irradiation with γ-rays orelectron rays is preferable, since any residue such as an initiator orthe like does not remain, and since the degree of penetration into thematerials is high.

The insolubilization, herein referred to, relates to the solubility ofthe crosslinked hollow fiber membrane in dimethylformamide. Theinsolubilization of the crosslinked membrane is evaluated as follows:1.0 g of the crosslinked membrane is cut out and then is dissolved in100 mL of dimethylformamide, and the insoluble portion of the membraneis visually observed for evaluation. In case of a module filled with aliquid, firstly, the liquid is removed; then, pure water is allowed topass through the passage on the side of a dialyzate at a rate of 500mL/min. for 5 minutes; then, similarly, pure water is allowed to passthrough the passage on the side of blood at a rate of 200 mL/min. for 5minutes; and finally, pure water is allowed to pass through the passagefrom the side of blood to the side of the dialyzate as if permeating themembrane, at a rate of 200 mL/min., so as to wash the membrane. Thehollow fiber membrane is removed from the resultant module and isfreeze-dried. This freeze-dried membrane is used as a sample formeasuring the insoluble component. Also, in case of a dried hollow fibermembrane module, the similar washing is done to prepare a sample formeasurement.

The inner surface of the hollow fiber membrane has a two-layer structureattributed to the difference in concentration of the hydrophilic polymerbetween the uppermost layer and the proximate layer. In the hollow fibermembrane, the sizes of pores therein tend to increase from the denselayer of the inner surface of the membrane toward the outer surfacethereof, and therefore, the inner surface of the membrane may have atwo-layer structure which has difference in density between theuppermost layer portion and the proximate layer portion. The thicknessof the respective layers and the interface therebetween optionallychanges depending on the conditions for manufacturing the hollow fibermembrane, and the structures of the layers give some influence on thecapacities of the hollow fiber membrane. While it can be recognized thatthere are seemingly two layers, i.e., the uppermost layer and theproximate layer, in the inner surface of the membrane, a definiteinterface can not be recognized between the uppermost layer and theproximate layer, in consideration of the situation where the two layersare almost concurrently formed adjacent to each other, when supposingthe manufacturing step of the hollow fiber membrane by way of thecoagulation thereof. When the distribution curves of the content of thehydrophilic polymer in the interface portion between the two layers areinvestigated, the distribution curves are connected like a continuousline in many cases. From this fact, it can be supposed that there may bedifference in concentration between the two layers, which is attributedto the difference in the content of the hydrophilic polymer. In general,a fault occurs in distribution curves of the content of the hydrophilicpolymer in the interface between the two layers, and therefore, thereare technical difficulties in the assumption of the formation of twodiscontinuous layers in which the materials therefor differently behave.It is the best to control the content of the hydrophilic polymer in theuppermost layer to 20 to 40 mass % and the content of the hydrophilicpolymer in the proximate layer to 5 to 20 mass %. However, the designingfor controlling the content of the hydrophilic polymer in the uppermostlayer to, for example, 40 mass % and the content of the hydrophilicpolymer in the proximate layer to, for example, 5 mass % may make itimpossible for the resultant membrane to sufficiently function, inconsideration of the mechanism in which the hydrophilic polymer diffusesand transfers from the proximate layer to the uppermost layer in thesurface of the membrane. In other words, it is also important to designthe membrane by paying attentions on the simple difference in thecontent of the hydrophilic polymer between the two layers. For example,the difference (the multiplying factor of at least 1.1) in the content(mass %) of the hydrophilic polymer between the uppermost layer and theproximate layer is converted into the difference in the mass % betweenthe contents of the hydrophilic polymer in the two layers. Then, thesimple difference in content of the hydrophilic polymer between therespective layers is adjusted to, preferably about 1 to about 35 mass %,optimally about 5 to about 25 mass %. Under this condition, thediffusion and transfer of the hydrophilic polymer from the proximatelayer to the uppermost layer of the surface of the membrane can proceedsmoothly. For example, when the content of the hydrophilic polymer inthe uppermost layer is 32 mass %, the content of the hydrophilic polymerin the proximate layer is 7 to 27 mass %, which satisfies the abovepreferable condition, i.e., the multiplying factor of about 1.1 to about10.

In this regard, the content of the hydrophilic polymer in the uppermostlayer of the hollow fiber membrane is measured and calculated by theESCA method as will be described later, and the absolute value of thecontent in the uppermost layer portion (having a depth of several toseveral tens angstrom from the surface layer) of the hollow fibermembrane is determined. In general, it is possible to measure thecontent of the hydrophilic polymer (e.g., polyvinyl pyrrolidone (PVP))present in a layer portion which has a depth of up to about 10 nm: (100angstrom) from the blood-contacting surface of the hollow fiber membraneby the ESCA method (uppermost layer ESCA).

In the meantime, the content of the hydrophilic polymer in the proximatelayer of the surface of the hollow fiber membrane is the result of theevaluation of the absolute value of the ratio of the hydrophilic polymerpresent in a layer portion which has a depth equivalent to severalhundreds nm. According to the ATR method (the proximate layer ATR), itis possible to measure the content of the hydrophilic polymer in a layerportion which has a depth of about 1,000 to about 1,500 nm (1 to 1.5 μm)from the blood-contacting surface of the hollow fiber membrane.

The contents of the hydrophilic polymer in the inner surface and theouter surface of the hollow fiber membrane may have some connection withthe molecular weight of the hydrophilic polymer. For example, polyvinylpyrrolidone having a lower molecular weight (about 450,000) shows ahigher solubility and is eluted in a larger amount in the coagulation ofa hollow fiber membrane, and largely diffuses and transfers, as comparedwith polyvinyl pyrrolidone having a high molecular weight (about1,200,000). For these reasons, there is formed a hollow fiber membranewhich has relatively high concentrations of the hydrophilic polymer,that is, 20 to 40 mass % of the hydrophilic polymer in the uppermostlayer portion and 5 to 20 mass % of the hydrophilic polymer in theproximate layer portion in the surface of the membrane, in comparisonwith an average mass ratio (1 to 20 mass %) of the hydrophilic polymerrelative to the polysulfone type polymer. A hollow fiber membrane may beformed using polyvinyl pyrrolidones having different molecular weightsin combination; for example, when a hollow fiber membrane ismanufactured from 80 mass % of a polysulfone type resin, and 15 mass %of a polyvinyl pyrrolidone having a molecular weight of 900,000 and 5mass % of a polyvinyl pyrrolidone having a molecular weight of about45,000, the contents of the polyvinyl pyrrolidones in the two layers andthe capacities of the hollow fiber membrane may sometimes be influenced.Designing of a hollow fiber membrane made from this point of view isalso included in the scope of the present invention.

To attain the foregoing features 2, 3 and 4 of the present invention,for example, the mass ratio of the hydrophilic polymer to thehydrophobic polymer is controlled within the above specified range, andthe conditions for manufacturing the hollow fiber membrane are optimallycontrolled. In concrete, preferably, a dense layer formed on the side ofthe inner surface of the hollow fiber membrane has a two-layer structurewhich has difference in density between the uppermost layer portion andthe proximate layer portion. When the mass ratio of the polysulfone typepolymer to the hydrophilic polymer in the spinning dope, and theconcentration and temperature of an interior-coagulating solution arecontrolled within ranges as will be explained later, the coagulatingrates and/or the phase-separating rates of the uppermost layer portionand the proximate layer portion of the inner surface of the hollow fibermembrane become different from each other, and also, the polysulfonetype polymer and the hydrophilic polymer become different from eachother in the solubility in a solvent/water. These differences areconsidered to exhibit the features 2 and 3, although the particularreasons therefor are not known.

Regarding the feature 4, the important point is to optimize theconditions for drying the hollow fiber membrane: when a wet hollow fibermembrane is dried, the hydrophilic polymer dissolved in water tends totransfer from the inner portion of the hollow fiber membrane to thesurface thereof, accompanying the transfer of the water. By employingdrying conditions as will be described later in this stage, it becomespossible to transfer water at a certain rate and also to make thewater-transferring rate constant in a whole of the hollow fibermembrane, so that the hydrophilic polymer in the hollow fiber membranecan immediately transfer to both the surfaces of the membrane withoutforming any spot. It is assumed that the amount of the hydrophilicpolymer transferring to the outer surface of the membrane is largeraccordingly, and thus, the feature 4 of the hollow fiber membrane of thepresent invention is attained, since the evaporation of water from theouter surface of the membrane is larger in amount than that from theinner surface thereof.

The mass ratio of the hydrophilic polymer to the polysulfone typepolymer in the spinning dope is preferably 0.1 to 0.6. When the contentof PVP in the dope is too small, it may become difficult to control therespective ratios of PVP in the membrane within the ranges specified bythe features 2, 3 and 4. Therefore, the ratio of the hydrophilic polymerto the polysulfone type polymer in the dope is preferably at least 0.15,more preferably at least 0.2, still more preferably at least 0.25, andparticularly at least 0.3. When the content of PVP in the dope is toolarge, the content of PVP in the membrane also becomes larger, whichrequires hard washing of the membrane, resulting in higher cost.Therefore, the ratio of PVP in the dope is more preferably 0.57 or less,still more preferably 0.55 or less.

The interior-coagulating solution is preferably an aqueous solution of15 to 70 mass % of dimethylacetamide (DMAc). When the concentration ofthe interior-coagulating solution is too low, the coagulating rate ofthe inner surface of the membrane becomes higher, which sometimes makesit hard to control the content of the hydrophilic polymer in theproximate layer of the inner surface of the membrane. Therefore, theconcentration of the interior-coagulating solution is more preferably 20mass % or more, still more preferably 25 mass % or more, far morepreferably 30 mass % or more. When the concentration of theinterior-coagulating solution is too high, the coagulating rate of theinner surface of the membrane becomes lower, which makes it hard tocontrol the content of the hydrophilic polymer in the uppermost layer ofthe inner surface of the membrane. Therefore, the concentration of theinterior-coagulating solution is more preferably 60 mass % or less,still more preferably 55 mass % or less, far more preferably 50 mass %or less. Further, it is preferable to control the temperature of theinterior-coagulating solution within a range of −20 to 30° C. When thetemperature of the interior-coagulating solution is too low, theuppermost layer of the surface of the membrane may coagulate immediatelyafter the extrusion of the hollow fiber membrane through the nozzle,which makes it hard to control the content of the hydrophilic polymer inthe proximate layer of the inner surface of the membrane. Therefore, thetemperature of the interior-coagulating solution is more preferably −10°C. or higher, still more preferably 0° C. or higher, far more preferably10° C. or higher. When the temperature of the interior-coagulatingsolution is too high, there may be too large a difference in themembrane structure (condensation and rarefaction) between the uppermostlayer and the proximate layer in the inner surface of the membrane,which makes it hard to control the contents of the hydrophilic polymerin the uppermost layer and the proximate layer in the inner surface ofthe membrane. Therefore, the temperature of the interior-coagulatingsolution is more preferably 25° C. or lower, still more preferably 20°C. or lower. By controlling the temperature of the interior-coagulatingsolution within the above specified range, it becomes possible toinhibit the bubbling of the gases dissolved in the interior-coagulatingsolution, when the interior-coagulating solution is extruded through thenozzle. By inhibiting the bubbling of the gasses dissolved in theinterior-coagulating solution, such secondary effects are produced thatthe breaking of the membrane just under the nozzle and the formation ofknobs on the membrane can be suppressed. To control the temperature ofthe interior-coagulating solution within the above specified range, itis preferable to provide a heat exchanger in the piping from theinterior-coagulating solution tank to the nozzle.

In one of specific preferred examples of drying wet hollow fibermembranes, a bundle of wet hollow fiber membranes is put in a microwavedrier and is dried under irradiation with microwave of 0.1 to 20 kW andunder a reduced pressure of 20 kPa or lower. The higher an output ofmicrowave is, the better, in consideration of the reduction of dryingtime. However, it is preferable not to excessively increase the outputof microwave, since the hydrophilic polymer in the hollow fibermembrane, if excessively dried or heated, is deteriorated or decomposed,or the membrane tends to lower in wettability in use. Therefore, theoutput of microwave is more preferably 18 kW or lower, still morepreferably 16 kW or lower, far more preferably 14 kW or lower. Whileeven lower than 0.1 kW of output of microwave is possible to dry abundle of hollow fiber membranes, longer drying time is required, whichmay lead to less treating amount. The output of microwave is thereforemore preferably 0.15 kW or higher, still more preferably 0.2 kW orhigher. The reduced pressure which is employed in combination with theoutput of microwave is more preferably 15 kPa or lower, still morepreferably 10 kPa or lower, which may vary depending on the moisturecontent of the bundle of the hollow fiber membranes, found before thedrying step. The lower the reduced pressure is, the better, since thedrying speed can be more quicker. However, the lower limit of thereduced pressure is preferably 0.1 kPa, more preferably 0.2 kPa orhigher, still more preferably 0.3 kPa or higher, in consideration of anincreased cost for improving the sealing degree of the system.Preferably, the optimum values of the output of microwave and thereduced pressure are determined by experiments, because such optimumvalues change depending on the moisture content of the bundle of hollowfiber membranes and the number of hollow fiber membranes in the bundle.

For example, the referential drying conditions of the present inventionare described: when a bundle of 20 hollow fiber membranes, each of whichhas a moisture content of 50 g per membrane, is dried, the totalmoisture content is 1,000 g (50 g×20=1,000 g), and the output ofmicrowave suitable for this total moisture content is 1.5 kW, and thereduced pressure suitable therefor is 5 kPa.

The frequency of the irradiated microwave is preferably 1,000 to 5,000MHz, more preferably 1,500 to 4,500 MHz, still more preferably 2,000 to4,000 MHz, in consideration of the inhibition of the formation ofirradiation spots on the bundle of hollow fiber membranes, and theeffect of pushing water out of the pores of the membranes.

It is important to uniformly heat and dry the bundle of hollow fibermembranes while the membranes being dried by the exposure of microwave.In this microwave drying, reflected waves incidental to the generationof microwaves cause non-uniform heating, and therefore, it is importantto employ a means for reducing the non-uniform heating which is causedby the reflected waves. Such a means is not limited and may be anoptional one: for example, a reflecting plate is provided in an oven toreflect the reflected waves thereon to thereby uniform the heating, asdisclosed in JP-A-2000-340356.

Preferably, the hollow fiber membranes are dried within 5 hours under acombination of the application of microwaves and under the above reducedpressure. When the drying time is too long, the transfer speed of waterin the hollow fiber membrane is low, which may give some influence onthe transfer of the hydrophilic polymer dissolved in the water. As aresult, it becomes impossible to transfer the hydrophilic polymer to theintended site (or layer) in the hollow fiber membrane, or spotsattributed to such transfer tend to occur, so that it may becomeimpossible to control the contents of the hydrophilic polymer in therespective sites (or layers). Therefore, the hollow fibermembrane-drying time is more preferably within 4 hours, still morepreferably within 3 hours. The shorter the drying time becomes, thebetter, because of the less transfer amount of the hydrophilic polymer.However, the drying time is preferably 5 minutes or longer, morepreferably 10 minutes or longer, still more preferably 15 minutes orlonger, when the frequency and output of microwave are suitably selectedin combination with the reduced pressure so as to prevent thedeterioration or decomposition of the hydrophilic polymer due to theheating and to inhibit the formation of spots during the drying step.

Further, the highest temperature of the hollow fiber membrane whilebeing dried is preferably 80° C. or lower. When this temperature is toohigh, there is a danger of the hydrophilic polymer's deterioration anddecompostion. Therefore, the temperature of the hollow fiber membranebeing dried is more preferably 75° C. or lower, still more preferably70° C. or lower. On the contrary, when this temperature is too low, thedrying time becomes longer, which may make it hard to control theamounts of the hydrophilic polymer in the respective sites of the hollowfiber membrane, as described above. Therefore, the drying temperature ispreferably 20° C. or higher, more preferably 30° C. or higher, stillmore preferably 40° C. or higher.

Further, it is preferable not to bone-dry the hollow fiber membrane. Ifbone-dried, the wettability of the hollow fiber membrane tends to lowerwhen the membrane is again wetted for use, or the hydrophilic polymerbecomes hard to absorb water and may be easily eluted from the hollowfiber membrane. Therefore, the moisture content of the dried hollowfiber membrane is preferably 1 wt. % or more, more preferably 1.5 wt. %or more. When the moisture content of the hollow fiber membrane is toohigh, the propagation of bacteria may be facilitated, or the hollowfiber membrane may be crushed by its own weight, during the storagethereof. Therefore, the moisture content of the hollow fiber membrane ispreferably 5 wt. % or less, more preferably 4 wt. % or less, still morepreferably 3 wt. % or less.

In the present invention, the rate of pore area of the outer surface ofthe hollow fiber membrane is preferably 8 to 25%, and the average porearea of the opened portion of the outer surface of the hollow fibermembrane is preferably 0.3 to 1.0 μm². These specific conditions areeffective to impart the above features to the hollow fiber membrane, andthus are preferred embodiments. When the rate of pore area is less than8% and when the average pore area is less than 0.3 μm², the coefficientof water permeability tends to lower. Further, such hollow fibermembranes tend to stick to one another due to the hydrophilic polymerpresent on the outer surfaces of the membranes while the membranes arebeing dried, and thus are hard to be incorporated into a module.Therefore, the rate of pore area is more preferably 9% or more, stillmore preferably 10% or more. The average pore area is more preferably0.4 μm² or more, still more preferably 0.5 μm² or more, far morepreferably 0.6 μm² or more. On the contrary, when the rate of pore areaexceeds 25% and when the average pore area exceeds 1.0 μm², the burstpressure tends to lower. Therefore, the rate of pore area is morepreferably 23% or less, still more preferably 20% or less, far morepreferably 17% or less, and particularly 15% or less. The average porearea is more preferably 0.95 μm² or less, still more preferably 0.90 μm²or less.

In order to control the content of the hydrophilic polymer and the rateof pore area of the outer surface of the hollow fiber membrane withinthe above specified ranges, the optimization of the conditions forwashing the manufactured hollow fiber membranes is also effective, inaddition to the adjustment of the mass ratio of the hydrophilic polymerto the polysulfone type polymer in the spinning dope and theoptimization of the conditions for drying the hollow fiber membranes. Asthe membrane-manufacturing conditions, it is effective to optimize thetemperature and humidity of the air gap of the outlet of a nozzle, thedope-drawing condition and the temperature and the composition of anexterior-coagulating bath. As the washing method, washing with hot wateror alcohol and centrifugal washing are effective. Above all, theoptimization of the humidity of the air gap and the composition ratio ofa solvent and a non-solvent in the exterior-coagulating bath isparticularly effective as the membrane-manufacturing conditions, and thewashing with alcohol is particularly effective as the washing method.

Preferably, the air gap is enclosed with a material capable of shieldingthe air gap from an external air. Preferably, the humidity inside of theair gap is controlled according to the composition of the spinning dope,the temperature of the nozzle, the length of the air gap, and thetemperature and composition of the exterior-coagulating bath. Forexample, a spinning dope (polyethersulufone/polyvinylpyrrolidone/dimethylacetamide/RO water=10 to 25/0.5 to 12.5/52.5 to89.5/0 to 10.0) is extruded through a nozzle of 30 to 60° C., and isthen allowed to pass through an air gap with a length of 100 to 1,000 mmand is guided to the exterior-coagulating bath which holds a solutionhaving a concentration of 0 to 70 mass % and a temperature of 50 to 80°C. In this case, the absolute humidity of the air gap is 0.01 to 0.3kg/kg dry air. By controlling the humidity of the air gap within thisrange, it becomes possible to control the rate of pore area, the averagepore area and the content of the hydrophilic polymer of the outersurface of the hollow fiber membrane within the proper ranges,respectively.

The exterior-coagulating solution is preferably an aqueous solution of 0to 50 mass % of DMAc. When the concentration of the exterior-coagulatingsolution is too high, the rate of pore area and the average pore area ofthe outer surface of the hollow fiber membrane become too large, whichmay induce a danger of accelerating the backflow of endotoxin to theside of blood during hemodialysis. Therefore, the concentration of theexterior-coagulating solution is more preferably 40 mass % or less,still more preferably 30 mass % or less, far more preferably 25 mass %or less. On the contrary, when the concentration of theexterior-coagulating solution is too low, a large amount of water isneeded to dilute the solvent which is brought from the spinning dope,and the cost for disposal of waste liquid increases. Therefore, thelower limit of the exterior-coagulating solution is more preferably 5mass % or more.

In the manufacturing of the hollow fiber membrane of the presentinvention, it is preferable not to substantially draw the hollow fibermembrane before the structure of the hollow fiber membrane has beenfixed. The wording of “not to substantially draw the hollow fibermembrane” means that the velocities of rollers used in the spinning stepare so controlled as not to loose or excessively pull a filament-likespinning dope extruded through a nozzle. The ratio of the linearvelocity of the extrusion to the velocity of the first roller in thecoagulating bath (draft ratio) is preferably 0.7 to 1.8. When this ratiois less than 0.7, the hollow fiber membrane being fed may be loosen,which leads to poor productivity. When this ratio exceeds 1.8, thestructure of the membrane may be destructed: for example, the denselayer of the hollow fiber membrane is spilt. The draft ratio is morepreferably 0.85 to 1.7, still more preferably 0.9 to 1.6, andparticularly 1.0 to 1.5. When the draft ratio is adjusted within thisrange, the deformation or destruction of pores can be prevented, and theclogging of the pores of the membrane with the protein in blood can beprevented. Thus adjusted, the hollow fiber membrane can exhibit stableperformance with time, and sharp fractional properties.

The hollow fiber membrane having passed through the water bath isdirectly wound in a wet state onto a hank, so as to make up a bundle of3,000 to 20,000 hollow fiber membranes. Then, the resulting bundle ofhollow fiber membranes is washed to remove the excessive solvent andhydrophilic polymer. In the present invention, preferably, the bundle ofhollow fiber membranes is immersed in hot water of 70 to 130° C., or anaqueous solution of 10 to 40 vol. % of ethanol or isopropanol of a roomtemperature to 50° C. for washing.

-   (1) In the washing with hot water, the bundle of hollow fiber    membranes is immersed in excessive RO water and treated at a    temperature of 70 to 90° C. for 15 to 60 minutes, and then is    removed from the bath and subjected to centrifugal dehydration. This    operation is repeated 3 or 4 times while RO water is being replaced.-   (2) The bundle of hollow fiber membranes immersed in excessive RO    water in a compressed container may be treated at 121° C. for about    2 hours.-   (3) In the washing with an aqueous solution of ethanol or    isopropanol, preferably, the same operation as the above    operation (1) is repeated.-   (4) Also preferably, the bundle of hollow fiber membranes is    radially laid in a centrifugal washing machine and is subjected to    centrifugal washing for 30 minutes to 5 hours, while washing water    is being shower-like blown thereonto at an angle of 40 to 90° from    the center of the rotation.

Each of the above washing methods may be carried out in combination withone or more of the above methods. When the treating temperature is toolow in any of the above methods, it is needed to increase the washingtimes in number, which may lead to higher cost. On the contrary, whenthe treating temperature is too high, the decomposition of thehydrophilic polymer is accelerated, and thus, the washing efficiency, onthe contrary, may become poor. By washing the bundle of hollow fibermembranes as above, the ratio of the hydrophilic polymer present on theouter surface of the membrane is properly controlled, which makes itpossible to inhibit the sticking of the membranes and to decrease theamount of eluted substances.

In the present invention, it is important to concurrently attain theforegoing features 1 to 4 to thereby make it possible to satisfy all theforegoing properties.

Because of having the foregoing features, the bundle of hollow fibermembranes of the present invention is preferably used in a bloodpurifier.

When used in a blood purifier, preferably, hollow fiber membranes havinga burst pressure of 0.5 MPa or higher are used, and the coefficient ofwater permeability of the blood purifier is 150 mL/m²/hr/mmHg or more.

The burst pressure herein referred to is an index of the pressureresistant capacity of hollow fiber membranes made into a module. Theburst pressure is measured as follows: the interior space of the hollowfiber membrane is compressed with an air while the compression pressureis being gradually increased, and a pressure which bursts the hollowfiber membrane when the membrane can not withstand the internal pressurethereof is measured. The higher the burst pressure is, the less thelatent defects of the hollow fiber membrane are which will cause cuttingand pin pores in the hollow fiber membrane in use. Therefore, the burstpressure is preferably 0.5 MPa or higher, more preferably 0.7 MPa orhigher and particularly 1.0 MPa or higher. When the burst pressure islower than 0.5 MPa, it may be impossible to detect such latent defectsof the hollow fiber membrane that leads to the leakage of blood as willbe described later. While a higher and higher burst pressure ispreferred, it may become impossible to obtain a desired membraneperformance, if the thickness of the membrane is increased or the voidratio is excessively decreased in order to increase the burst pressure.Therefore, the burst pressure is preferably lower than 2.0 MPa, morepreferably lower than 1.7 MPa, still more preferably lower than 1.5 MPaand particularly lower than 1.3 MPa, when the hollow fiber membranes areused in a hemodialyzer.

In the mean time, when the coefficient of water permeability is lessthan 150 mL/m²/hr/mmHg, the solute permeability tends to lower. When thesize or the number of the pores of the membrane is increased in order toimprove the solute permeability, the strength of the membrane tends tolower or defects are caused in the membrane. In one of the preferredhollow fiber membranes of the present invention, a decreased resistanceto solute-permeation and an improved strength of the membrane can beconcurrently achieved in good balance by optimizing the pore size of theouter surface of the membrane, thereby optimizing the void ratio of thesupport layer portion in the outer surface of the membrane. Thecoefficient of water permeability is more preferably 200 mL/m²/mmHg ormore, still more preferably 300 mL/m²/mmHg or more, far more preferably400 mL/m²/mmHg or more, and particularly 500 mL/m²/mmHg or more. On theother hand, when the coefficient of water permeability is too high, thewater-removing control during a hemodialysis therapy becomes hard.Therefore, the coefficient of water permeability is preferably 2,000mL/m²/mmHg or less, more preferably 1,800 mL/m²/mmHg or less, still morepreferably 1,500 mL/m²/mmHg or less, far more preferably 1,300mL/m²/mmHg or less, and particularly 1,000 mL/m²/mmHg or less.

In the final stage for providing a commercial product, a module for usein blood purification is usually subjected to a leak test in which theinterior or the exterior of a hollow fiber is pressurized with an air inorder to check any defect of the hollow fiber or the module. When a leakis detected by the compressed air, such a module is scraped as adefective or such a defect is repaired. The air pressure for use in theleak test is, in many cases, several times larger than the proofpressure of hemodialyzers (generally 500 mmHg). Microflaws, crushing orsplitting of very highly water permeable hollow fiber membranes for usein blood purification, which can not be detected by any of theconventional pressurizing leak tests, cause the cutting or pin pores ofthe hollow fiber membranes, in the course of the manufacturing stepsafter the leak test (mainly in the step of sterilization or packing), inthe course of transporting, or in the course of handling in a clinicalsite (unpacking or priming); and such cutting or pin pores in themembranes cause troubles such as the leakage of blood during a therapy.These troubles can be avoided by specifying the burst pressure as above.

The non-uniformity in thickness of hollow fiber membranes is alsoeffective to suppress the occurrence of the foregoing latent defects.The non-uniformity in thickness means the non-uniformity of thethickness of 100 hollow fiber membranes in a module, when the sectionsof the hollow fiber membranes are observed. The smaller the value of thenon-uniformity indicated by a ratio of a maximum value of the thicknessto a minimum value thereof, the better. Preferably, the non-uniformityper 100 hollow fiber membranes is 0.6 or more. When even only one hollowfiber membrane having a non-uniformity of smaller than 0.6 is includedin 100 follow fiber membranes, such a hollow fiber membrane may cause alatent defect which will lead to the leakage of blood during a clinicaltherapy. Therefore, the non-uniformity referred to in the presentinvention is not an average value of non-uniformity of the 100 followfiber membranes but a minimum value thereof. The higher thenon-uniformity, the better, because the uniformity of the membranes isimproved to thereby suppress the manifestation of latent defects of themembranes, which leads to an increase in the burst pressure. Therefore,the non-uniformity is more preferably 0.7 or more. When thenon-uniformity is smaller than 0.6, the latent defects of the membranestend to occur as actual defects, so that the burst pressure becomeslower and that the leakage of blood from the membranes tends to occur.

To control the non-uniformity in the thickness of the membrane to 0.6 ormore, for example, it is preferable to strictly uniform the width of theslit of a nozzle, namely, the outlet for discharging themembrane-forming solution. Generally used as a spinning nozzle forhollow fiber membranes is a tube-in-orifice type nozzle which has anannular portion for discharging a spinning dope and a hole for extrudingan interior-coagulating solution for forming a hollow portion, insidethe annular portion. The width of the slit indicates the width of theouter annular portion for discharging the spinning dope. By lesseningthe variation of the width of the slit, the non-uniformity of thethickness of a spun hollow fiber membrane can be decreased.Specifically, the ratio of a maximum value to a minimum value of thewidth of the slit is controlled to 1.00 to 1.11, and preferably, thedifference between the maximum value and the minimum value is adjustedto 10 μm or less, more preferably 5 μm or less. Also effective are theoptimization of the temperature of the nozzle, the decrease of spots ofthe interior-coagulating solution formed in the course of manufacturingmembranes, the optimization of the multiplying factor of the drawing,etc.

To further increase the burst pressure, the flaws of the surfaces of thehollow fiber membranes and the foreign matters and bubbles included inthe membranes are lessened to thereby decrease the latent defects of themembranes. To prevent the occurrence of flaws on the membranes, it iseffective to optimize the conditions of the materials for rollers andguides used in the steps of manufacturing hollow fiber membranes, andthe roughness of the surfaces of the materials. It is also effective todecrease the number of times of contact between a module casing and thehollow fiber membranes or the number of frictions between each of thehollow fiber membranes, when the bundle of the hollow fiber membranes isincorporated into the module. In the present invention, the rollers tobe used is preferably planished at their surfaces in order to preventthe hollow fiber membranes from slipping and having flaws on thesurfaces thereof. The surfaces of the guides to be used are preferablymatte-finished or knurly finished to reduce the resistance attributed tothe contact with the hollow fiber membranes as much as possible. Thebundle of hollow fiber membranes is not directly inserted into themodule casing, but preferably, the bundle of hollow fiber membraneswrapped in a matte-finished film is inserted in the module casing, andthen, only the film is removed from the module casing.

To prevent the hollow fiber membranes from including foreign matters, itis effective to use materials containing less foreign matters, or todecrease the amount of foreign matters by filtering the spinning dopefor forming the membranes. In the present invention, the spinning dopeis preferably filtered through a filter having pores with a diametersmaller than the thickness of the hollow fiber membranes. Specifically,the spinning dope which is homogeneously dissolved is allowed to passthrough a sintered filter which has pores with diameters of 10 to 50 μmand which is located on a passage along which the spinning dope isguided from the dissolution tank to the nozzle. The filtering may bedone at least once, however, it is preferable to make the filteringtreatment in a plurality of steps using filters whose pores becomesmaller in diameter in the latter steps, in order to improve thefiltering efficiency and to prolong the life of the filter. The diameterof the pores of the filter is preferably 10 to 45 μm, more preferably 10to 40 μm. When the diameter of the pores of the filter is too small, theback pressure increases, and the quantitative evaluation degrades.

To prevent the inclusion of bubbles in the membranes, it is effective todegass the polymer solution for forming membranes. Stationary degassingor decompression degassing may be employed in accordance with theviscosity of the spinning dope. In concrete, the inner space of adissolution tank is decompressed to −100 to −760 mmHg, and then issealed, and the tank is left to stand in a still state for 5 to 30minutes. This operation is repeated several times for degassing thetank. When the decompression degree is too low, it may be needed toincrease the number of times of degassing, which requires longer time.When the decompression degree is too high, high cost is often needed toimprove the sealing degree of the system. The total time for thedegassing treatment is preferably 5 minutes to 5 hours. When thetreating time is too long, the hydrophilic polymer may be deterioratedor decomposed due to the decompression effect. When the treating time istoo short, the effect of degassing may become poor.

EXAMPLES

Hereinafter, the present invention will be explained by way of Examplesthereof, which should not be construed as limiting the scope of thepresent invention in any way. The methods of evaluating the physicalproperties of the following Examples are described below.

1. Coefficient of Water Permeability

The circuit on the side of the blood outlet in a dialyzer (on the sideof the outlet from a pressure-measuring point) was blocked with aforceps. A compression tank was charged with pure water maintained at37° C., and the pure water was fed to the blood passage of the dialyzerinsulated in a constant-temperature bath of 37° C. while the pressure inthe bath was being controlled with a regulator, and the mass of afiltrate flowing out of the side of the dialyzate passage was measured.The difference in pressure between each of the membranes (TMP) isexpressed by the equation:TMP=(Pi+Po)/2[in the equation, Pi represents the pressure on the side of the inlet ofthe dialyzer; and Po, the pressure on the side of the outlet thereof].The TMP was varied at four points, and the flow amount of the filtrationwas measured, and the coefficient of water permeability (mL/hr·/mmHg)was calculated from the gradient indicting the relationship between TMPand the flow amount of the filtration. At this point of time, thecoefficient of correlation between TMP and the flow amount of thefiltration must be 0.999 or more. To reduce an error in pressure lossdue to the circuit, TMP was measured within a pressure range of 100 mmHgor lower. The coefficient of water permeability of the hollow fibermembrane was calculated from the area of the membrane and thecoefficient of water permeability of the dialyzer:UFR(H)=UFR(D)/A[in the equation, UFR(H) represents the coefficient of waterpermeability (mL/m²/hr/mmHg) of the hollow fiber membrane; UFR(D)represents the coefficient of water permeability (mL/hr/mmHg) of thedialyzer; and A represents the area (m²) of the membrane in thedialyzer].2. Calculation of the Area of Membranes

The area of membranes in the dialyzer was calculated based on the innerdiameter of the hollow fiber membrane as a reference:A=n×π×d×L[in the equation, n represents the number of hollow fiber membranes inthe dialyzer; π represents the ratio of the circumference of a circle toits diameter; d represents the inner diameter (m) of the hollow fibermembrane; and L represents the effective length (m) of the hollow fibermembrane in the dialyzer].3. Burst Pressure

The dialyzate side of a module comprising about 10,000 hollow fibermembranes was filled with water and was then capped. A dry air ornitrogen was fed from the blood side of the module at a room temperatureso as to compress the module at a rate of 0.5 MPa/min. The pressure wasincreased so that the hollow fiber membranes were burst by thecompressed air. Then, the air pressure was measured, when bubblesoccurred in the liquid filling the dialyzate side of the module,simultaneously with the bursting of the membranes. This air pressure wasdefined as a burst pressure.

4. Non-Uniformity in Thickness

The sections of 100 hollow fibers were observed with a projector of amagnification of 200. One hollow fiber which had portions whose sectionshad the largest difference in thickness was selected from 100 hollowfibers in one field of view, and the largest thickness and the smallestthickness of this hollow fiber were measured.The non-uniformity in thickness =the thickness of the thinnestportion/the thickness of the thickest portionIn this regard, the thickness of a membrane is perfectly uniform whenthe non-uniformity of thickness is one (=1)5. Amount of Hydrophilic Polymer Eluted

A method of measuring the amount of polyvinyl pyrrolidone, as ahydrophilic polymer, eluted from a membrane is described.

<Dry Hollow Fiber Membrane Module>

A physiological saline was allowed to pass through the passage on theside a dialyzate in a module, at a rate of 500 mL/min. for 5 min., andthen was allowed to pass through the passage on the side of blood, at arate of 200 mL/minutes. After that, the physiological saline was allowedto flow from the side of blood to the side of the dialyzate at a rate of200 mL/minute for 3 min. while being filtered.

<Wet Hollow Fiber Membrane Module>

The liquid was removed from the module, and the same operation as wasdone on the dry hollow fiber membrane module was repeated.

Extraction was made on the hollow fiber membrane module which had beensubjected to the above priming treatment, according to the methodregulated in the approved criteria for manufacturing dialyzer typeartificial kidney, and polyvinyl pyrrolidone in the extract wasdetermined by a calorimetric method.

In detail, pure water (100 mL) was added to the hollow fiber membranes(1 g), and extraction was made on the hollow fiber membranes at 70° C.for one hour. To the resultant extract (2.5 mL), a 0.2 mol aqueouscitric acid solution (1.25 mL) and a 0.006N aqueous iodine solution (0.5mL) were added, and the mixture was sufficiently mixed and was left tostand alone at a room temperature for 10 minutes. After that, theabsorbance of the mixture was measured at 470 nm. The determination wasmade using polyvinyl pyrrolidone as a sample, based on the analyticalcurve determined by the measurement according to the above method.

6. Contents of Hydrophilic Polymer in Uppermost Layers of Inner andOuter Surfaces of Membrane

The content of a hydrophilic polymer was determined by the X-rayphotoelectron spectroscopy (ESCA method). Analysis using polyvinylpyrrolidone (PVP) as a hydrophilic polymer is herein explained.

One hollow fiber membrane (obliquely cut with a cutter so as to expose apart of the inner surface of the membrane) was applied on a sample tableto be analyzed by the ESCA method. The conditions for the analysis wereas follows:

Apparatus: ULVAC-PHI ESCA5800

Excitation X-ray: MgKα ray

X-ray output: 14 kV, 25 mA

Escape angle of photoelectron: 45°

Analyzed diameter: 400 μmφ

Pass energy: 29.35 eV

Resolution: 0.125 eV/step

Degree of vacuum: about 10⁻⁷ Pa or lower

The content of PVP in the surface of the membrane was calculated fromthe found value of nitrogen (N) and the found value of sulfur (S), bythe following equation.

<Membrane of PES (Polyethersulfone) Admixed with PVP>Content of PVP (Hpvp)[mass %]=100×(N×111)/(N×111+S×232)<Membrane of PSf (Polysulfone) Admixed with PVP>Content of PVP (Hpvp)[mass %]=100×(N×111)/(N×111+S×442)7. Content of Hydrophilic Polymer in a Whole of Hollow Fiber Membrane

Measurement using PVP as a hydrophilic polymer is described as one ofexamples. A sample was dried with a vacuum drier at 80° C. for 48 hours,and 10 mg of the dried sample was analyzed with a CHN coder (Model MT-6,manufactured by YANAKO BUNSEKI KOGYOSHA). The mass ratio of PVP wascalculated from the content of nitrogen by the following equation.The mass ratio of PVP (mass %)=the content of nitrogen (mass %)×111/148. Content of Hydrophilic Polymer in Proximate Layer of Surface ofHollow Fiber Membrane on Blood-Contacting Side

Measurement using PVP as a hydrophilic polymer is described as one ofexamples. The measurement was conducted by an infrared absorbinganalysis. A sample made up in the same manner as in the above item 6 wasused. The content of PVP in the proximate layer of the surface of thesample membrane was measured by the ATR method, and the content of PVPin a whole of the membrane was measured by the transmission method. Inthe ATR method, an infrared absorption spectrum was measured by using adiamond 45° as an internal reflecting element. Model IRμs/SIRMmanufactured by SPECTRA TECH was used for the measurement. The ratio ofthe absorption intensity Ap of the peak derived from C═O of PVC at andaround 1675 cm⁻¹ in the infrared absorption spectrum, to the absorptionintensity As of the peak derived from a polysulfone type polymer at andaround 1580 cm⁻¹, i.e., Ap/As, was determined. In the ATR method, theabsorption intensity depends on the measured wave number. Therefore, asa correction value, the ratio of the position of the peak νs of thepolysulfone type polymer and the position of the peak νp (wave number)of PVP, i.e., νp/νs was measured. The content of PVP in the proximatelayer in the surface of the membrane on the blood-contacting side wascalculated by the following equation:Content (mass %) of Hydrophilic Polymer in Proximate Layer of Surface ofMembrane=Cav×(Ap/As)×(νp/νs)

In this equation, Cav is the mass ratio of PVP determined by “Content ofHydrophilic Polymer in a Whole of Hollow Fiber Membrane” mentionedabove.

9. Rate of Pore Area of Outer Surface of Hollow Fiber Membrane

The outer surface of a hollow fiber membrane was observed with anelectron microscope of a magnification of 10,000 and photographed (SEMphotograph). The obtained image was processed with an image analysisprocessing soft to determine the rate of pore area of the outer surfaceof the hollow fiber membrane. For example, “Image Pro Plus” (MediaCybernetics, Inc.) was used as the image analysis processing soft formeasurement. The fetched image was subjected to an emphasis and filteroperation so as to discriminate the pore portions from the closedportions. After that, the number of the pores was counted. If polymerchains of the lower layer were observed in the interiors of the pores,such pores were combined and regarded as one pore. The total (B) of thearea (A) within the measured range and the area of the pores within themeasured range was calculated, and the rate of pore area (%) wascalculated by the equation: the rate of pore area (%)=(B/A)×100. Thiscalculation was repeated with respect to 10 fields of view, and anaverage of the results was found. Scale-setting was carried out as theinitiating operation, and the pores on the boundary around the measuredrange were not excluded from the counting.

10. Average Pore Area of Open Portion of Outer Surface of Hollow FiberMembrane

Counting was made in the same manner as in the above operation, tocalculate the area of each pore. The pores on the boundary around themeasured range were excluded from the counting. This calculation wasrepeated with respect to 10 fields of view, and an average of all thepore areas was calculated.

11. Blood Leak Test

Bovine blood of 37° C. of which the coagulation was inhibited by theaddition of citric acid was fed to a blood purifier at a rate of 200mL/min., and was filtered at a rate of 20 mL/min. The resulting filtratewas returned to the blood to make a circulating system. After 60 minuteshad passed, the filtrate in the blood purifier was collected, and thereddish tone of the filtrate due to the leakage of blood cell wasvisually observed. This blood leak test was conducted using 30 bloodpurifiers in each of Examples and Comparative Examples, and the numberof modules from which blood leaked was counted.

12. Sticking of Hollow Fiber Membranes

About 10,000 hollow fibers were bundled, and the bundle thereof was setin a module casing of 30 to 35 mmφ. The module casing was sealed with atwo-pack type polyurethane resin to make up a module. The leak test wasconducted on 5 standard modules. After that, the number of the modulesfrom which the blood leaked due to the defect in the sealing with theurethane resin was counted.

13. Blood Residue in Hollow Fiber Membrane

The side of a dialyzate of a module having a membrane area of 1.5 m² wasfilled with physiological saline. A blood bag charged with 200 mL ofheparinized blood collected from a healthy person was connected to themodule through a tube, and the blood was allowed to circulate at a flowrate of 100 mL/minute at 37° C. for one hour. The blood was sampledbefore the start of circulation and 60 minutes after the start ofcirculation, respectively, to count the number of white blood cells andthe number of blood platelets. The counted values were corrected byhematocrit values.Corrected value=Counted value (60 mins.)×Hematocrit (0 min.)/Hematocrit(60 mins.)

The rates of change of the white blood cells and the blood plateletswere calculated from the corrected value.Rate of Change=Corrected value (60 mins.)/the value before the start ofcirculation×100

After the completion of the circulation for 60 minutes, the bloodtreated with the physiological saline was retransfused, and the numberof the hollow fibers having the blood left to remain therein wascounted. The evaluation criteria were based on the number of the hollowfibers having the blood left to remain therein.

10 or less: ◯

11 to 30: Δ

31 or more: X

14. Priming Capacity

Distilled water for injection solution was allowed to flow at a rate 200mL/min. from the inlet port on the side of blood, while the port on theside of a dialyzate being capped. The distilled water was degassed bytapping the module casing 5 times with forcepts for 10 seconds from thepoint of time when the distilled water had reached the outlet port.After that, the number of bubbles passing through for one minute wasvisually counted. The evaluation criteria were based on the number ofbubbles observed:

10 or less/min.: ◯

11 to 30/min.: Δ

30 or more/min.: X

Example 1

Polyethersulfone (SUMIKAEXCEL®4800P, manufactured by Sumika Chem TexCo., Ltd.) (17.6 mass %), polyvinyl pyrrolidone (COLIDONE®K-90manufactured by BASF) (4.8 mass %), dimethylacetamide (DMAc) (74.6 mass%) and RO water (3 mass %) were homogeneously dissolved at 50° C., andthen, the system was vacuumed up to −500 mmHg with a vacuum pump. Afterthat, the system was immediately sealed so as not to change thecomposition of the membrane-forming solution due to the evaporation ofthe solvent or the like, and the system in this state was left to standalone for 15 minutes. This operation was repeated three times so as todegas the membrane-forming solution. This solution was allowed to passthrough sintered filters with pore sizes of 30 μm and 15 μm in twostages, and then was extruded from the outer slit of a tube-in-orificenozzle heated to 65° C. Simultaneously with this extrusion, an aqueoussolution of DMAc (45 mass %) of 15° C. as an interior-coagulatingsolution which had been previously degassed for 60 minutes under apressure of −700 mmHg was extruded from the hole for theinterior-coagulating solution. Then, the solution was allowed to passthrough a drying zone with a length of 450 mm, which was shielded froman external air by a spinning tube, and then was coagulated in anaqueous solution of DMAc (20 mass %) heated to 60° C. The resultantmembrane in a wet state was directly wound onto a hank. The slit of thetube-in-orifice nozzle used had an average width of 60 μm, a maximumwidth of 61 μm and a minimum width of 59 μm, and the ratio of themaximum value to the minimum value of the width of the slit was 1.03.The draft ratio of the membrane-forming solution was 1.06.

A bundle of about 10,000 hollow fiber membranes as obtained above waswrapped in a polyethylene film which was matte-finished at its surfaceon the side of the bundle, and then was cut into bundles of the hollowfiber membranes with lengths of 27 cm. This bundle was washed in hotwater of 80° C. for 30 minutes. This washing was repeated 4 times. Thebundle of the wet membranes was subjected to centrifugal dehydration at600 rpm for 5 minutes, and each 12 bundles of the membranes were set oneach of two-staged turn tables in the drying apparatus and were exposedto microwaves of initial 1.5 kW with a microwave-generating apparatus inwhich reflecting plates were provided in the oven for uniform heating.Simultaneously with this operation, the interior space of the dryingapparatus was vacuumed to 7 kPa with a vacuum pump, so as to dry thebundles of membranes for 28 minutes. Sequentially, the bundles ofmembranes were dried under the application of microwaves with an outputof 0.5 kW and under reduced pressure 7 kPa for 12 minutes. The output ofmicrowave was decreased to 0.2 kW, under which the bundles of membraneswere similarly dried for 8 minutes. Thus, the drying of the bundles ofmembranes was completed. In addition, this drying was carried out by themicrowave application in combination with far infrared radiation. Thehighest temperature of the surface of the bundle of membranes at thistime was 65° C., and the moisture content of the dried hollow fibermembrane was 2 mass % on average. The inner diameter of the hollow fibermembrane was 199.1 μm, and the thickness thereof was 28.5 μm. Therollers used, with which the hollow fiber membranes came into contactduring the spinning step, were planished at their surfaces, and all theguides used were matte-finished at their surfaces.

A blood purifier was made up of the hollow fiber membranes thusobtained, and was used for leak tests. As a result, no failure inadhesion, attributed to the sticking of the hollow fiber membranes, wasobserved.

The blood purifier was filled with RO water, and was irradiated withγ-rays of an absorbed dose of 25 kGy for crosslinking the membranes.After the γ-ray irradiation, the hollow fiber membranes were cut outfrom the blood purifier, and the cut pieces of the hollow fibermembranes were subjected to an elution test. As a result, the amount ofthe eluted PVP was 4 ppm, which was in the level of no problem. Further,the outer surfaces of the hollow fiber membranes removed from the bloodpurifier were observed with a microscope. As a result, any defect suchas flaws or the like was not observed.

Fresh bovine blood admixed with citric acid was allowed to pass throughthe blood purifier at a flow rate of 200 mL/min. and at a filtering rateof 10 mL/min. As a result, no leakage of blood cells was observed. Theamount of endotoxin filtered from the outside of the hollow fibermembrane to the inside thereof was smaller than the limit for detection,which was in the level of no problem. The results of other analyses areshown Table 1.

Comparative Example 1

Wet hollow fiber membranes were obtained in the same manner as inExample 1, except that the amounts of polyvinyl pyrrolidone(COLIDONE®K-90 manufactured by BASF) and DMAC of a spinning dope werechanged to 2.4 mass % and 77 mass %, respectively, and that a dryingzone with a length of 700 mm was used. The resultant hollow fibermembranes were washed in the same manner as in Example 1, and dried in ahot air drier of 60° C. The moisture content of the resultant hollowfiber membrane was 3.4 mass %, and the inner diameter thereof was 199.5μm, and the thickness thereof was 29.8 μm. The characteristics of theresultant bundle of hollow fiber membranes and the resultant bloodpurifier are shown in Table 1. Many of the hollow fiber membranes ofComparative Example 1 had the blood left to remain therein. This wasbecause the content of PVP in the proximate layer of the inner surfaceof this membrane was low.

Comparative Example 2

A spinning dope was obtained in the same manner as in Example 1, exceptthat the amount of PVP (COLIDONE®K-90 manufactured by BASF) was changedto 12.0 mass %, and the amount of DMAc, to 67.4 mass %. Further, abundle of hollow fiber membranes and a blood purifier were obtained inthe same manners as in Example 1, except that the temperature of thevoid-forming agent was not controlled, that the hollow fiber membraneswere not washed, and that the bundle of hollow fiber membranes was driedin the same manner as in Comparative Example 1. The characteristics ofthe resultant bundle of hollow fiber membranes and the resultant bloodpurifier are shown in Table 1. The hollow fiber membrane obtained inthis Comparative Example had a higher content of PVP in the uppermostlayer of the inner surface thereof, and the amount of eluted PVA waslarger. In addition, the permeation of endotoxin into the blood side wasobserved because of the higher content of the hydrophilic polymer in theouter surface of the hollow fiber membrane.

Comparative Example 3

A bundle of hollow fiber membranes and a blood purifier were obtained inthe same manners as in Comparative Example 2, except that the time ofthe hot water washing was changed to 6 hours. The characteristics of theresultant bundle of hollow fiber membranes and the resultant bloodpurifier are shown in Table 1. The hollow fiber membrane obtained inthis Comparative Example had a lower content of PVP in the uppermostlayer of the outer surface thereof, and thus, the priming capacity wasinferior due to the lower hydrophilicity of the outer surface thereof.

Example 2

Polyethersulfone (SUMIKAEXCEL®4800P, manufactured by Sumika Chem TexCo., Ltd.) (18.8 mass %), polyvinyl pyrrolidone (COLIDONE®K-90manufactured by BASF) (5.2 mass %), DMAc (71.0 mass %) and water (5 mass%) were dissolved at 50° C., and then, the system was vacuumed up to−700 mmHg with a vacuum pump. After that, the system was immediatelysealed so as not to change the composition of the membrane-formingsolution due to the evaporation of the solvent or the like, and thesystem in this state was left to stand alone for 10 minutes. Thisoperation was repeated three times so as to degas the membrane-formingsolution. This solution was allowed to pass through filters with poresizes of 15 μm and 15 μm in two stages, and then was extruded from theouter slit of a tube-in-orifice nozzle heated to 70° C. Simultaneouslywith this extrusion, an aqueous solution of DMAc (55 mass %) of 10° C.as an interior-coagulating solution which had been previously degassedfor 2 hours under a pressure of −700 mmHg was extruded from the hole forthe interior-coagulating solution. The resultant hollow fiber membranewas allowed to pass through an air gap with a length of 330 mm, whichwas blocked from an external air by a spinning tube, and then wascoagulated in water of 60° C. The slit of the tube-in-orifice nozzleused had an average width of 45 μm, a maximum width of 45.5 μm and aminimum width of 44.5 μm, and the ratio of the maximum value to theminimum value of the width of the slit was 1.02. The draft ratio of themembrane-forming solution was 1.06. The absolute humidity of the dryingzone was 0.12 kg/kg dry air. The hollow fiber membrane removed from thecoagulating bath was allowed to pass through a water bath of 85° C. for45 seconds to remove the solvent and the excessive hydrophilic polymer,and then was wound up. A bundle of about 10,000 hollow fiber membranesas obtained above was wrapped in the same polyethylene film as that usedin Example 1, and then was immersed in an aqueous solution of 40 vol. %of isopropanol of 30° C. for 30 minutes. This immersion was repeatedtwice, and this aqueous solution was replaced with water.

The bundle of the wet hollow fiber membranes was subjected tocentrifugal dehydration at 600 rpm for 5 minutes, and each 48 bundles ofthe membranes were set on each of turn tables in two stages in thedrying apparatus and were exposed to microwaves of initial 7 kV.Simultaneously with this operation, the interior space of the dryingapparatus was vacuumed to 5 kPa with a vacuum pump, so as to dry thebundles of membranes fro 65 minutes. Sequentially, the bundles ofmembranes were dried under the application of microwaves with an outputof 3.5 kV and under reduced pressure of 5 kPa for 50 minutes. The outputof microwave was decreased to 2.5 kW, under which the bundles ofmembranes were similarly dried for 10 minutes. Thus, the drying of thebundles of membranes was completed. The highest temperature of thesurface of the bundle of membranes at this drying treatment was 65° C.,and the moisture content of the dried hollow fiber membrane was 2.8 mass% on average. The rollers used for changing the fiber path in thespinning step were planished at their surfaces, and all the guides usedwere matte-finished at their surfaces. The inner diameter of the hollowfiber membrane was 200.5 μm, and the thickness thereof was 28.2 μm.

A blood purifier was made up of the hollow fiber membranes thusobtained, and was used for leak tests. As a result, no failure inadhesion, attributed to the sticking of the hollow fiber membranes, wasobserved.

The blood purifier was subjected to the following analyses, without acrosslinking treatment of the hydrophilic polymer. The hollow fibermembranes were cut out from the blood purifier which had not beenirradiated with γ-rays, and the cut pieces of the hollow fiber membraneswere subjected to an elution test. As a result, the amount of the elutedPVP was 7 ppm, which was in the good level. Further, the outer surfacesof the hollow fiber membranes were observed with a microscope. As aresult, any defect such as flaws or the like was not observed.

In a blood leak test using bovine blood, no leakage of blood cells wasobserved. The amount of the endotoxin filtered from the outside of thehollow fiber membrane to the inside thereof was smaller than the limitfor detection, which was in the level of no problem. The results ofother analyses are shown Table 1.

Comparative Example 4

Polyethersulfone (SUMIKAEXCEL®7800P, manufactured by Sumika Chem TexCo., Ltd.) (23 mass %), PVP (COLIDONE®K-30 manufactured by BASF) (7 mass%), DMAc (67 mass %) and water (3 mass %) were dissolved at 50° C., andthen, the system was vacuumed up to −500 mmHg with a vacuum pump. Afterthat, the system was immediately sealed so as not to change thecomposition of the membrane-forming solution due to the evaporation ofthe solvent or the like, and the system in this state was left to standalone for 30 minutes. This operation was repeated twice so as to degasthe membrane-forming solution. This solution was allowed to pass throughfilters with pore sizes of 30 μm and 30 μm in two stages, and then wasextruded from the outer slit of a tube-in-orifice nozzle heated to 50°C. Simultaneously with this extrusion, an aqueous solution of DMAc (50mass %) of 50° C. as an interior-coagulating solution which had beenpreviously degassed under reduced pressure was extruded. The resultanthollow fiber membrane was allowed to pass through an air gap with alength of 350 mm, which was blocked from an external air with a spinningtube, and then was coagulated in water of 50° C. The slit of thetube-in-orifice nozzle used had an average width of 45 μm, a maximumwidth of 45.5 μm and a minimum width of 44.5 μm, and the ratio of themaximum value to the minimum value of the width of the slit was 1.02.The draft ratio of the membrane-forming solution was 1.06. The absolutehumidity of the drying zone was 0.07 kg/kg dry air. The hollow fibermembrane removed from the coagulating bath was allowed to pass through awater bath of 85° C. for 45 seconds to remove the solvent and theexcessive hydrophilic polymer, and then was wound up. A bundle of 10,000hollow fiber membranes as obtained above was directly dried at 60° C.for 18 hours, without washing. Sticking of the dried hollow fibermembranes was observed. It was impossible to make up a blood purifier ofthe hollow fiber membranes thus obtained, since an adhesive resin couldnot be successfully inserted between each of the hollow fiber membranes,when making up the blood purifier. The results of the analyses are shownTable 1.

Comparative Example 5

Polyethersulfone (SUMIKAEXCEL®4800P, manufactured by Sumika Chem TexCo., Ltd.) (20 mass %), triethyleneglycol (manufactured by MISTUICHEMICALS, INC.) (40 mass %), and N-methyl 2-pyrrolidone (manufacturedby Mitsubishi Chemical Corporation) (40 mass %) were mixed and stirredto prepare a homogeneous and transparent membrane-forming solution. Ahollow fiber membrane was obtained in the same manner as in Example 2,except that this membrane-forming solution and N-methyl2-pyrrolidone/triethyleneglycol/water (=5/5/90) as a void-formingmaterial were used. The inner diameter of the hollow fiber membrane was195 μm; the thickness thereof was 51.5 μm; the moisture content thereofwas 0.4 mass %; and the mass ratio of the hydrophilic polymer was 0 mass%.

This hollow fiber membrane had no problem in the amount of the elutedhydrophilic polymer and showed no sticking thereof and no backflow ofendotoxin, but could not be used as a membrane for hemodialysis. Thereasons therefor were that the hollow fiber membrane showed stronghydrophobic properties because of containing no hydrophilic polymer, andthat the protein in blood clogged the pores of the membrane and wasaccumulated on the surface of the membrane.

Example 3

Polysulfone (P-3500 manufactured by AMOCO) (18.5 mass %), polyvinylpyrrolidone (K-60 manufactured by BASF) (9 mass %), DMAc (67.5 mass %)and water (5 mass %) were dissolved at 50° C. Then, the inner space ofthe system was vacuumed up to −300 mmHg with a vacuum pump, and then wasimmediately sealed so as not to change the composition of themembrane-forming solution due to the evaporation of the solvent or thelike and left to stand alone for 15 minutes. This operation was repeatedthree times to degas the membrane-forming solution. The resultantmembrane-forming solution was allowed to pass through filters with poresizes of 15 μm and 15 μm in two stages, and then was extruded throughthe outer slit of a tube-in-orifice nozzle heated to 40° C.Simultaneously with this extrusion, an aqueous solution of 35 mass % ofDMAc of 0° C. as a void-forming agent which had been previously degassedunder reduced pressure was extruded through the inner hole of thetube-in-orifice nozzle. The resultant hollow fiber membrane was allowedto pass through an air gap with a length of 600 mm which was shieldedfrom an external air by a spinning tube, and then was coagulated inwater of 50° C. The slit of the tube-in-orifice nozzle had an averagewidth of 60 μm, a maximum width of 61 μm and a minimum width of 59 μm;the ratio of the maximum value to the minimum value of the width of theslit was 1.03; the draft ratio was 1.01; and the absolute humidity ofthe drying zone was 0.06 kg/kg dry air. The hollow fiber membraneremoved from the coagulating bath was allowed to pass through a waterbath of 85° C. for 45 seconds so as to remove the solvent and theexcessive hydrophilic polymer, and then was wound up. A bundle of 10,500hollow fiber membranes thus obtained was immersed in pure water, andthen washed in an autoclave at 121° C. for one hour. After the washing,the bundle of hollow fiber membranes was wrapped in the samepolyethylene film as that used in Example 1, and then was dried in thesame manner as in Example 1. The rollers used for changing the fiberpath in the spinning step were planished at their surfaces, and thestationary guides were matt-finished at their surfaces. The innerdiameter of the resultant hollow fiber membrane was 201.3 μm, and thethickness thereof was 44.2 μm.

The hollow fiber membranes thus obtained were used to make up a bloodpurifier for use in a leak test. As a result, no failure in adhesion dueto the sticking of the hollow fiber membranes was observed.

The resultant blood purifier was filled with RO water and irradiatedwith γ rays of an absorbed dose of 25 kGy to crosslink the hydrophilicpolymer. The hollow fiber membranes were cut out of the blood purifierafter the irradiation with γ rays, and were subjected to an elutiontest. As a result, the amount of the eluted PVP was 8 ppm, which was inthe level of no problem. In addition, the outer surfaces of the hollowfiber membranes were observed with a microscope, and were found to haveno defect such flaws or the like.

Fresh bovine blood admixed with citric acid was allowed to pass throughthe blood purifier at a flow rate of 200 mL/min. and at a filtering rateof 10 mL/min., with the result of no leakage of red blood cells. Theamount of endotoxin filtered from the outer side to the inner side ofthe hollow fiber membrane was smaller than the limit for detection,which was in the level of no problem. The results of other analyses areshown in Table 1.

Example 4

Polysulfone (P-1700 manufactured by AMOCO) (17 mass %), polyvinylpyrrolidone (K-60 manufactured by BASF) (4.8 mass %), DMAc (73.2 mass %)and water (5 mass %) were dissolved at 50° C. Then, the inner space ofthe system was vacuumed up to −400 mmHg with a vacuum pump, and then wasimmediately sealed so as not to change the composition of themembrane-forming solution due to the evaporation of the solvent or thelike, and was left to stand alone for 30 minutes. This operation wasrepeated three times to degas the membrane-forming solution. Theresultant membrane-forming solution was allowed to pass throughtwo-stepped filters with pore sizes of 15 μm and 15 μm, and then wasextruded through the outer slit of a tube-in-orifice nozzle heated to40° C. Simultaneously with this extrusion, an aqueous solution of 35mass % of DMAc of 0° C. as an interior-coagulating solution which hadbeen previously degassed under reduced pressure was extruded through theinner hole of the tube-in-orifice nozzle. The resultant hollow fiber wasallowed to pass through an air gap with a length of 600 mm which wasshielded from an external air by a spinning tube, and then wascoagulated in water of 50° C. The slit of the tube-in-orifice nozzle hadan average width of 60 μm, a maximum width of 61 μm and a minimum widthof 59 μm; the ratio of the maximum value to the minimum value of thewidth of the slit was 1.03; the draft ratio was 1.01; and the absolutehumidity of the drying zone was 0.07 kg/kg dry air. The hollow fibermembrane removed from the coagulating bath was allowed to pass through awater bath of 85° C. for 45 seconds so as to remove the solvent and theexcessive hydrophilic polymer, and then was wound up. A bundle of 10,700hollow fiber membranes thus obtained was immersed in pure water, andthen washed in an autoclave at 121° C. for one hour. After the washing,the bundle of hollow fiber membranes was wrapped in a polyethylene film,and then was dried in the same manner as in Example 2. The rollers usedfor changing the fiber path in the spinning step were planished at theirsurfaces, and the guides were matt-finished at their surfaces. The innerdiameter of the resultant hollow fiber membrane was 201.2 μm, and thethickness thereof was 43.8 μm.

The bundle of the hollow fiber membranes thus obtained was used to makeup a blood purifier for use in a leak test. As a result, no failure inadhesion due to the sticking of the hollow fiber membranes was observed.The resultant blood purifier was filled with RO water and irradiatedwith γ rays of an absorbed dose of 25 kGy to crosslink the hydrophilicpolymer.

The hollow fiber membranes were cut out of the blood purifier after theirradiation with γ rays, and were subjected to an elution test. As aresult, the amount of the eluted PVP was 4 ppm, which was in the levelof no problem. In addition, the outer surfaces of the hollow fibermembranes were observed with a microscope, and were found to have nodefect such flaws or the like.

Fresh bovine blood admixed with citric acid was allowed to pass throughthe blood purifier at a flow rate of 200 mL/min. and at a filtering rateof 10 mL/min., with the result of no leakage of red blood cells. Theamount of endotoxin filtered from the outer side to the inner side ofthe hollow fiber membrane was smaller than the limit for detection,which was in the level of no problem. The results of other analyses areshown in Table 1.

INDUSTRIAL APPLICABILITY

The polysulfone type hollow fiber membranes of the present invention arereliable in safety and stability of performance and are easilyincorporated into a module, and thus are suitable for use in hollowfiber type blood purifiers which are required to have highly waterpermeability to be used for therapy of chronic renal failure. Thus, thepresent invention will significantly contribute to the industry of thisfield.

TABLE 1 Com. Com. Com. Com. Com. Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 1 Ex. 2 Ex.3 Ex. 4 Ex. 5 Coefficient of water 589 383 622 416 565 337 367 — 1210permeability (ml/m²/hr/mmHg) Burst pressure (MPa) 0.6 0.7 1.1 0.9 0.60.6 0.6 — 0.7 Non-uniformity in 0.75 0.90 0.83 0.87 0.76 0.73 0.71 —0.88 thickness (ratio) Leakage of blood (number 0 0 0 0 0 0 0 — 0 ofmodules) Amount of eluted PVP 4 7 8 4 6 21 11 14 — (ppm) Content of PVPin 25 22 35 30 18 45 39 28 — uppermost layer of inner surface ofmembrane [A] (mass %) Content of PVP in 11 12 17 18 4 26 21 9 —proximate layer of inner surface of membrane [C] (mass %) [A]/[C] 2.271.83 2.06 1.67 4.5 1.73 1.86 3.11 — Content of PVP in 36 27 39 40 19 4123 57 — uppermost layer of outer surface of membrane [B] (mass %)[B]/[A] 1.44 1.23 1.11 1.33 1.06 0.91 0.59 2.04 — PVP/PSf in membrane4.3 3.9 7.6 3.9 2.5 13.2 8.8 10.5 — Average pore area of 0.6 0.5 0.8 0.60.4 0.3 0.4 0.2 0.1 outer surface of membrane (μm²) Rate of pore area of18 19 13 22 20 11 12 5 9 outer surface of membrane (%) Moisture content(mass %) 2.0 2.8 1.7 1.7 3.4 4.5 2.6 1.9 0.5 PVP/PSf in dope 0.27 0.280.49 0.28 0.27 0.68 0.68 0.30 — Number of membranes stuck 0 0 0 0 0 17 030 0 Permeation of endotoxin ND ND ND ND ND Some ND — ND Insolublecomponent Some None Some Some Some Some Some None None Blood left toremain in ◯ ◯ ◯ ◯ X ◯ ◯ — X membrane Priming capacity ◯ ◯ ◯ ◯ ◯ ◯ X — X

1. A selectively permeable hollow fiber membrane comprising apolysulfone-based resin and a hydrophilic polymer as main components,wherein (A) the content of the hydrophilic polymer in the uppermostlayer of an inner surface of the hollow fiber membrane is at least 1.1times the content of the hydrophilic polymer in the proximate layer ofsaid inner surface, and (B) the content of the hydrophilic polymer inthe uppermost layer of an outer surface of the hollow fiber membrane isat least 1.1 times the content of the hydrophilic polymer in theuppermost layer of said inner surface.
 2. The hollow fiber membrane ofclaim 1, wherein said uppermost layer of the inner surface of the hollowfiber membrane is a layer between the inner surface and a positionpresent at a depth of 10 nm from the inner surface, and wherein saidproximate layer is a layer between the inner surface and a positionpresent at a depth of 1,000 to 1,500 nm (1 to 1.5 μm) from the innersurface.
 3. The hollow fiber membrane of claim 1, wherein the content ofthe hydrophilic polymer in the hollow fiber membrane is 20 to 40 mass %at the uppermost layer of the inner surface of the membrane, 5 to 20mass % at the proximate layer thereof, and 25 to 50 mass % at theuppermost layer of the outer surface of the membrane.
 4. The hollowfiber membrane of claim 1, comprising 99 to 80 mass % of thepolysulfone-based resin and 1 to 20 mass % of the hydrophilic polymer asthe main components.
 5. The hollow fiber membrane of claim 1, whereinthe hydrophilic polymer is polyvinyl pyrrolidone.
 6. The hollow fibermembrane of claim 1, wherein the amount of the hydrophilic polymereluted from the hollow fiber membrane is 10 ppm or less.
 7. The hollowfiber membrane of claim 1, wherein the rate of pore area of the outersurface of the hollow fiber membrane is 8% to less than 25%.
 8. Thehollow fiber membrane of claim 1, wherein the hydrophilic polymer iscrosslinked so as to be insoluble in water.
 9. A blood purifiercomprising at least one hollow fiber membrane of claim 1.